Bone Marrow Derived Mesenchymal Stem Cells in Addiction Related Hippocampal Damages

The brain is an important organ that controls all sensory and motor actions, memory, and emotions. Each anatomical and physiological modulation in various brain centers, results in psychological, behavioral, and sensory-motor changes. Alcohol and addictive drugs such as opioids and amphetamines have been shown to exert a great impact on brain, specifically on the hippocampus. Emerging evidence has indicated that altered hippocampal neurogenesis is associated with the pathophysiology of neuropsychological disorders including addiction. The addictive drugs impair neurogenesis and undermine the function of neural stem/progenitor cells in hippocampus. This feature was claimed to be one of the underlying mechanisms of behavioral changes in patients with addiction. As the impairment of stem cells’ function has been proven to be the underlying cause of pathologic neuroadaptations in the brain, the administration of stem cell populations has shown promising results for re-modulating of neuronal status in the brain and especially in the hippocampus. Among the different types of stem cells, bone marrow derived mesenchymal stem cells are the most proper candidates for stem cell therapies. In this review article, the recent studies on the effects of addictive drugs on brain neurogenesis, and also the promising potential effects of stem cells in curing addiction related hippocampal damages are discussed.

the brain, where granular cells in the dentate gyrus are born in adulthood. The precursors of these cells are placed in the subgranular zone (SGZ), the tissue between hilus and granule cell layer (3,4). The sensible characteristic of adult-born neurons in the hippocampus is their specific electrophysiological capability for extreme changes required in early stages of maturation. This property is pivotal for formation of memories and further physiological actions (5). The SGZ provides a proper niche for proliferation and differentiation of stem cells in dentate gyrus (6). Astrocytes as important cellular components of SGZ, play an active role in proliferation and neuronal fate commitment of NSPCs (7) through release of molecular signals such as Wnt (8), Ephrin B2 (9), and sonic hedgehog (Shh) (10,11). Moreover, they have been shown to play essential roles in neural cell survival, immune responding, and modulation and metabolism of neurotransmitters (12). Therefore, each stimulant that can affect NSPCs or their niche in the hippocampus could make a vast modification in the memory and behavior. Bulk of studies have found the alterations in adult neurogenesis of hippocampus in neuropsycho-logical disorders such as depression (13), schizophrenia (14), bipolar disease (15), and addiction (16). A large amount of evidence indicates the changes in adult neurogenesis of dentate gyrus in abusing drugs such as opioids (17), amphetamines (18), and alcohol (19).

Addictive drugs and alcohol can regulate
NSPCs by a variety of mechanisms. Some of these mechanisms are shared among them (16). For example, they regulate adult neurogenesis by modulating cell cycling pathways (20), and G protein-coupled receptor (GPCR) signaling cascades (21). Moreover, molecules involved in supporting or inhibiting neurogenesis including brain-derived neurotrophic factor (BDNF), interleukin 1 beta (IL1β) or vascular endothelial growth factor (VEGF), could be influenced by some addictive drugs (22). Additionally, they can exacerbate mitochondrial function and invoke oxidative stress (23). There is an evidence that 4hydroxynonenal (HNE), an aldehydic product of membrane lipid peroxidation, is a key mediator of neuronal apoptosis induced by oxidative stress (24).
Some signaling molecules and pathways such as the mitogen-activated protein kinase (MAPK) signaling pathway, cell cycle regulatory molecules, and microRNAs (miRNAs) which may function independently or act in conjunction with one another have been identified to play important roles in these modulations (25).
Although neurons are the principal targets of drug addiction, it has recently been shown that nearly all drugs of abuse also affect glial cells (26).
Astrocytes as the most abundant glial cells in brain (27)  Neurogenesis in the dentate gyrus decreased markedly in amphetamine-treated rats following four weeks of withdrawal from amphetamine (47).
Neuroinflammation is also associated with the chronic use of addictive drugs including cocaine, opiates, marijuana, and methamphetamine (48).
It is vital to indicate that all above studies show a correlation between daily drug intake and alteration in neurogenesis. As the amount of drug intake increases, the pathologic effects are more on the dentate gyrus neurogenesis.

Alcohol-associated alterations in the neurogenesis in hippocampus
Alcohol abuse often leads to the alcohol use disorder (AUD) that has great deteriorating impacts on the brain. Excessive use of alcohol results in progressive neurodegeneration in brain that also accelerates AUD (49). Alcohol abuse causes general changes in white and gray matters in the central nervous system (50)(51)(52); nevertheless, some brain centers are more affected by alcohol abuse.
Ethanol neurotoxicity greatly disturbs hippocampus and frontal cortex (52,53). The altered integrity of hippocampus in alcoholics leads to abnormal cognitive functions and psychopathological actions (54,55), which further results in AUD development (55,56).  More studies on the stem cell therapy of psychological defects related to addiction are required.

Conflict of interest
The authors declare no conflict of interest.